@article{789df9f34e454b0c872738c4b8824726,
title = "Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study",
abstract = "Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.",
keywords = "Alzheimer disease, Genome-wide association study, Non-demented elderly with AD neuropathology, Non-demented elderly without AD neuropathology, Reelinneurofibrillary tangles",
author = "Kramer, {Patricia L.} and Haiyan Xu and Woltjer, {Randall L.} and Westaway, {Shawn K.} and David Clark and Deniz Erten-Lyons and Kaye, {Jeffrey A.} and Welsh-Bohmer, {Kathleen A.} and Troncoso, {Juan C.} and Markesbery, {William R.} and Petersen, {Ronald C.} and Turner, {R. Scott} and Kukull, {Walter A.} and Bennett, {David A.} and Douglas Galasko and Morris, {John C.} and Jurg Ott",
note = "Funding Information: The authors would like to thank the following individuals for their generous and varied contributions to the production of this report, including clinical and neuropathological data verification, DNA and brain tissue procurement and transportation, and data organization and transmission: Charles DeCarli MD, at the University of California at Davis; Marilyn Albert MD, at Johns Hopkins University; Christine Hulette MD, James Burke MD, Jeffrey Browndyke PhD, John Ervin, Michelle McCart and Mari Szmanski RN at Duke University Medical Center; Alison Goate PhD, at the Washington University School of Medicine; Joseph Parisi MD and Kris Johnson RN, at Mayo Clinic, Rochester, and Dennis Dixon at Mayo Clinic, Jacksonville; Sonya Anderson at the University of Kentucky; Mary Sundsmo at the University of California at San Diego; Eszter Gombosi at the University of Michigan; Jamie Laut at Oregon Health & Science University. We thank Dr. Chungsheng He, Rockefeller University, for writing an R program to create the Manhattan plot. This work was supported by the National Institute on Aging (grants R01-AG026916 , P30-AG028377 , P50-AG005146 , P30-AG028383 , P50-AG16574 , U01-AG06786 , P30-AG008017 , P30-AG10161 , R01-AG17917 , P30-AG10129 , P50-AG05131 , P50-AG08671 , P50-AG05681 , P01-AG03991 , U01-AG016976 ) of the National Institutes of Health, and by the Natural Science Foundation of China NSFC, project number and 30700442 (to JO).",
year = "2011",
month = dec,
doi = "10.1016/j.neurobiolaging.2010.01.010",
language = "English",
volume = "32",
pages = "2113--2122",
journal = "Neurobiology of Aging",
issn = "0197-4580",
number = "12",
}